Oxazolidin-2-one derivatives, preparation method therefor and therapeutical use thereof

ABSTRACT

Compounds derived from oxazolidin-2-one of formula (I) ##STR1## in which: R 1  represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a fluoroalkyl group, a hydroxyfluoroalkyl group, a cyanoalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenylmethyl group or an R 3  A- group in which R 3  is a cycloalklyl or cyclooxyalkyl group which is unsubstituted or substituted by a hydroxyl group and A is a --CH 2  or --CH 2  --CH 2  radical, 
     R 2  represents a hydrogen atom or a methyl group, 
     X represents an oxygen or sulphur atom or an NR 4  group where R 4  is an alkyl group or a hydrogen atom, and 
     Z represents an oxygen atom or a --CH═CH or --CH 2  --CH 2  group, 
     their process of preparation and their applications in therapeutics.

This application is a 371 of PCT/FR96/01511 filed Oct. 8, 1996.

The subject of the present invention is compounds derived fromoxazolidin-2-one of general formula (I) ##STR2## in which: R₁ representsa hydrogen atom, an alkyl group, a hydroxyalkyl group, a fluoroalkylgroup, a hydroxyfluoroalkyl group, a cyanoalkyl group, a phenyl groupwhich is unsubstituted or substituted by a halogen atom or by an alkoxy,nitrile or nitro group, a phenylmethyl group which is unsubstituted orsubstituted by a halogen atom or by an alkoxy, nitrile or nitro group oran R₃ A- group in which R₃ is a is cycloalkyl or cyclooxyalkyl groupwhich is unsubstituted or substituted by a hydroxyl group and A is a--CH₂ or --CH₂ --CH₂ radical,

R₂ represents a hydrogen atom or a methyl group,

X represents an oxygen or sulphur atom or an NR₄ group where R₄ is analkyl group or a hydrogen atom and

Z represents an oxygen atom or a --CH═CH or --CH₂ --CH₂ group,

their process of preparation and their therapeutic applications.

In the context of the present invention, and except when otherwiseindicated, the above terms have the following meanings:

an alkyl group is a linear or branched saturated aliphatic groupcomprising 1 to 5 carbon atoms,

an alkoxy group is an OR₅ group, where R₅ is an alkyl group as definedabove,

a fluoroalkyl group is an alkyl group as defined above, at least one ofthe carbon atoms of which is substituted by one or a number of fluorineatoms,

a hydroxyfluoroalkyl group is a fluoroalkyl group as defined above, oneof the carbon atoms of which is substituted by a hydroxyl group,

a cycloalkyl group is a radical derived from a cycloalkane comprisingfrom 3 to 6 carbon atoms,

a cyclooxyalkyl group is a cycloalkyl group as defined above, one of thecarbon atoms of which is replaced by an oxygen atom as heteroatom; theperhydrofuranyl and perhydropyranyl groups are representative of such acyclooxyalkyl group,

a cyanoalkyl group is an alkyl group as defined above, at least one ofthe carbon atoms of which is substituted by a nitrile group.

The compounds of formula (I) where R₂ is a methyl group are preferred.Among the latter compounds, those where X represents an oxygen atom arevery particularly preferred.

When X represents an oxygen atom, the R₁ Z group advantageouslyrepresents:

either, i) an R_(a) O group, where R_(a) has one of the meanings of R₁chosen from a hydrogen atom, an alkyl group, a fluoroalkyl group, ahydroxyfluoroalkyl group, a cyanoalkyl group, an R₃ A- group, a phenylgroup which is unsubstituted or substituted by a halogen atom or anitro, nitrile or alkoxy group and a phenylmethyl group which isunsubstituted or substituted by a halogen atom or a nitro, nitrile oralkoxy group. More preferentially, R_(a) is a hydrogen atom or aphenylmethyl, butyl, 4,4,4-trifluorobutyl,4,4,4-trifluoro-3-hydroxybutyl, 3,3,3-trifluoro-2-hydroxypropyl,3-cyanopropyl, p-fluorophenylmethyl, cyclopropylmethyl or2-(1-hydroxycyclopentyl)ethyl group.

or, ii) an R_(b) Z group, where Z is a --CH═CH-- or --CH--CH₂ - groupand Re has one of the meanings of R₁ chosen from a hydrogen atom or analkyl group, a fluoroalkyl group, a hydroxyalkyl group, ahydroxyfluoroalkyl group, a phenyl group which is unsubstituted orsubstituted by a halogen atom or a nitro, nitrile or alkoxy group or aphenylmethyl group which is unsubstituted or substituted by a halogenatom or a nitro, nitrile or alkoxy group. More preferentially, R_(b) Zis chosen from the ethenyl, 2-phenylethenyl, 2-phenylethyl,5,5,5-trifluoropentyl, 5,5,5-trifluoropentenyl,5,5,5-trifluoro-4-hydroxypentyl or 5,5,5-trifluoro-4-hydroxypentenylgroup.

When X represents a sulphur atom, the R₁ Z group advantageouslyrepresents an R_(c) O group, where R, has one of the meanings of R₁chosen from an alkyl group, a hydroxyalkyl group, a fluoroalkyl group, ahydroxyfluoroalkyl group, a phenyl group which is unsubstituted orsubstituted by a halogen atom or a nitro, nitrile or alkoxy group or aphenylmethyl group which is unsubstituted or substituted by a halogenatom or by an alkoxy, nitrile or nitro group. According to a preferredaspect of the invention, R_(c) is chosen from the group consisting ofbutyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl and thephenylmethyl group.

When X represents an NR₄ group, R₄ is preferably a methyl group and theR₁ Z group advantageously represents an R_(d) O group, where R_(d) hasone of the meanings of R₁ chosen from a fluoroalkyl group, ahydroxyfluoroalkyl group, a phenyl group which is unsubstituted orsubstituted by a halogen atom or a nitro, nitrile or alkoxy group or aphenylmethyl group which is unsubstituted or substituted by a halogenatom or a nitro, nitrile or alkoxy group. According to a preferredaspect of the invention, R_(d) is chosen from the group consisting of4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl and thephenylmethyl group.

The compounds of formula (I) contain one or two asymmetric carbon atoms.They can therefore exist in the form of pure enantiomers ordiastereoisomers or of a mixture of these different forms, including aracemic mixture. These different forms, and their mixtures, form part ofthe invention.

The compounds of formula (I) in which R₁ Z represents an R₁ --CH═CH--group, with the exception of the compounds in which R₁ is a hydrogenatom, exist in the form of cis or trans isomers. These forms, and theirmixtures, form part of the invention.

The compounds of the invention of formula (I) can be prepared accordingto the processes described in Appendices 1 and 2.

The compounds of formulae (Ia), (Ib), (Ic), (Id) and (Ie), which arecompounds of formula (I) according to the invention where Z representsan oxygen atom, can be prepared according to the process represented inAppendix 1. In these compounds, X has one of the meanings given in theformula (I). According to this process, an ethyl carbamate derivative offormula (II) is reacted with 4-(methoxymethyl)-1,3-dioxolan-2-one offormula (III) in the presence of potassium carbonate. In the formula(II), R₁ and X have one of the meanings given in the formula (I) withthe exception, as regards R₁, of hydrogen. This reaction makes itpossible to obtain a compound of formula (Ia), which is a compound offormula (I) in which R₂ represents a methyl group and R₁ has one of themeanings given in the formula (I), with the exception of hydrogen.

The compounds of formula (Ia) where R₁ represents a phenylmethyl groupcan be used to prepare the compounds of formula (Ib). The latter arecompounds of formula (I) in which R₁ represents a hydrogen atom and R₂represents a methyl group. To this end, the phenylmethyl group of thesaid compound of formula (Ia) is removed by means, for example, ofdimethylphenylamine and of aluminium chloride or by catalytichydrogenation in the presence of palladium-on-charcoal.

The compounds of formula (Ib) can be used to prepare the compounds offormula (Ic). The latter are compounds of formula (I) in which R₁ and R₂each represent a hydrogen atom.

To do this, a compound of formula (Ib) is demethylated by means of aLewis acid, such as boron tribromide, in a solvent such asdichloromethane.

The compounds of formula (Ic) can, in their turn, be used to preparecompounds of formula (Id). The latter are compounds of formula (I) inwhich R₁ has one of the meanings given in the formula (I), with theexception of the hydrogen atom, and R₂ is a hydrogen atom. To do this, acompound of formula (Ic) can be reacted with a compound of formula R₁ Y,where R₁ has one of the meanings given in the formula (I), with theexception of hydrogen, and Y is a halogen atom or a labile group, suchas methylsulphonyloxy (mesyloxy) or p-toluenesulphonyloxy (tosyloxy).This reaction can be carried out in the presence of a base, such aspotassium carbonate, in a solvent, such as acetonitrile,N,N-dimethylformamide or a mixture of these solvents. The reactiontemperature can be the reflux temperature of the solvent.

According to an advantageous aspect of the invention, the compounds offormula (Ib) can be used to obtain compounds of formula (Ie) accordingto the invention in which R₁ has one of the meanings given in theformula (I), with the exception of the hydrogen atom meaning. To thisend, a compound of formula (Ib) is reacted with a compound of formula R₁Y, where R₁ has one of the meanings given in the formula (I), with theexception of a hydrogen atom, and Y is as defined above. This reactioncan be carried out in the presence of a base, such as potassiumcarbonate, in a solvent such as acetonitrile. The reaction temperaturecan be the reflux temperature of the solvent. The compound of formula(Ie) thus obtained can then be demethylated to prepare a compound offormula (Id). The demethylation can be carried out under the conditionsindicated above as regards the demethylation of the compound of formula(Ib). Of course, a compound (Ia) which already exhibits the desiredmeaning of R₁ has not to be converted to a compound (Ie); such acompound of formula (Ia) can itself be demethylated to obtain a compoundof formula (Id) directly.

According to another aspect of the invention, the compounds of formula(I) in which the R₁ group is a group comprising a hydroxyl functionalgroup can be prepared by reacting a compound of formula (II) containingsuch an R₁ group with a compound of formula (III), the said hydroxylfunctional group being protected beforehand, in a conventional way forthe person skilled in the art, by a protective group, such ast-butyldimethylsilyl. After preparing the compound of formula (Ia), theprotective group can be removed from the hydroxyl functional group bymeans, for example, of tetra-n-butylammonium fluoride, in an organicsolvent such as tetrahydrofuran.

The compounds of formulae (If) and (Ig), which are compounds of formula(I) according to the invention where Z represents, respectively, a--CH═CH or --CH₂ --CH₂ group, can be prepared according to the processrepresented in Appendix 2. In these compounds, X has one of the meaningsindicated in the formula (I).

According to this process, a compound of formula (Ib), as mentionedabove, is reacted with trifluoromethanesulphonic anhydride (Tf₂ O) toobtain a trifluoromethanesulphonate derivative of formula (IV).

The compound of formula (IV) can then be reacted with palladium acetatein the presence of carbon monoxide and of methanol to prepare amethoxycarbonyl derivative of formula (V), which is treated, in itsturn, by means of a borane-dimethyl sulphide complex (BH₃.S(CH₃)₂) toobtain a hydroxymethyl derivative of formula (VI). The latter can thenbe treated with oxalyl chloride and dimethyl sulphoxide to prepare aformyl derivative of formula (VII). This treatment can be carried out ata temperature of the order of -70° C.

The formyl derivative of formula (VII) can then be reacted with atriphenylphosphonium salt of formula R₁ CH₂ P⁺ (C₆ H₅)₃ W⁻, inparticular a triphenylphosphonium halide, such as a triphenylphosphoniumbromide, where R₁ has one of the meanings given in the formula (I) andW⁻ represents the anion of a halogen atom. This reaction can be carriedout in the presence of a base, such as potassium carbonate. A compoundaccording to the invention of formula (If) can thus be prepared in whichZ represents a --CH═CH-- group.

The compound of formula (If) can then be reduced to prepare a compoundaccording to the invention of formula (Ig). This reduction can becarried out by means of hydrogen in the presence of a catalyst, such aspalladium-on-charcoal. In the compounds of formulae (IV), (V), (VI) and(VII), X has one of the meanings given in the formula (I). The compoundsof formulae (If) and (Ig) can be demethylated to result in thecorresponding compounds of formula (I) where R₂ represents a hydrogenatom. This demethylation can be carried out by means of a Lewis acid,such as boron tribromide.

According to an advantageous aspect of the invention, the compounds offormula (If) in which R₁ is a hydrogen atom can be prepared directly byreacting the compound of formula (IV) mentioned above withtributylvinyltin in the presence of lithium chloride and oftetrakis(triphenylphosphine)palladium.

The compounds of formula (II) can be prepared according to the processrepresented in Appendix 3 by reacting a compound of formula (VIII) witha compound of formula R₁ Y, in which R₁ is defined as in the formula (I)with the exception of hydrogen and Y is a halogen atom, in particularbromine, or a labile group, such as methylsulphonyloxy (mesyloxy) orp-toluenesulphonyloxy (tosyloxy). This reaction can be carried out inthe presence of a base, such as potassium carbonate, in a solvent suchas acetonitrile. The reaction temperature can be the reflux temperatureof the solvent.

The compound of formula (VIII) can be prepared from a compound offormula (IX), where R₆ is a protective group for the hydroxyl group, inparticular a methyl or phenylmethyl group. To this end, the saidprotective group R₆ is removed by means which are conventional for theperson skilled in the art. Thus, when R₆ is a methyl group, the compoundof formula (IX) is demethylated by means of a Lewis acid, such as borontribromide, in an organic solvent such as dichloromethane. Thetemperature employed during this treatment can be between -20° C. and20° C. When R₆ is a phenylmethyl group, this protective group can beremoved by catalytic hydrogenation. Of course, when the protective groupR₆ has one of the desired meanings of R₁, the compound of formula (IX)can be used directly as compound of formula (II).

The compound of formula (IX) can be prepared by decarboxylation of acompound of formula (X), by heating at a temperature in the region ofthe melting point of the latter compound, indeed at a temperaturegreater than the said melting point.

The compound of formula (X) can be prepared by saponification of acompound of formula (XI) by means of a base, such as potassiumhydroxide, in alcoholic medium. The saponification reaction can becarried out at a temperature of between 0° C. and the reflux temperatureof the solvent. In the formula (XI), R₇ represents a methyl or ethylgroup.

The compound of formula (XI) can be prepared by reacting a compound offormula (XII), where R₇ represents a methyl or ethyl group, with ethylchloroformate. This reaction can be carried out in the presence of abase, such as potassium carbonate, in a solvent such as toluene. Thisreaction can be carried out at the reflux temperature of the solvent.

In each of the compounds of formulae (VIII), (IX), (X), (XI) and (XII),X has one of the meanings given in the formula (I).

The compounds of formula (XII) can be prepared according to varioussynthetic routes depending on the nature of X. These synthetic routesare represented in Appendix 4.

The compounds of formula (XII) where X is a sulphur atom and R₆ and R₇each represent a methyl group can be prepared by reacting3-nitro-4-cyanoanisole with methyl thioglycolate. This reaction can becarried out in the presence of a base, such as potassium hydroxide, in asolvent such as N,N-dimethylformamide. This reaction can be carried outat 0° C.

3-Nitro-4-cyanoanisole is a known compound. It can be prepared accordingto the process described by A. H. Cook et al., J. Chem. Soc., 1945, 68,861.

The compounds of formula (XII) in which X is an oxygen atom or NR₄ canbe prepared by a process according to which a compound of formula (XIII)is treated either with sodium ethoxide, when X represents an oxygenatom, or with potassium tert-butoxide, when X represents NR₄.

The compound of formula (XIII) can be prepared by reacting a compound offormula (XIV), where X is an oxygen atom or NR₄, with sodium hydride andthen ethyl bromoacetate.

A compound of formula (XIV) where X is an oxygen atom can be prepared byreacting 2-hydroxy-4-(phenylmethoxy)benzaldehyde with nitroethane orhydroxylamine and ethyl formate. 2-Hydroxy-4-(phenylmethoxy)benzaldehydeis a known compound which can be prepared according to J. S. H. Davies(J. Chem. Soc., 1950, 3206).

A compound of formula (XIV) where X is an NR₄ group can be prepared byreacting a compound of formula (XV) with a compound of formula R₄ NH₂,such as methylamine. The compound of formula (XV) can itself be obtainedby reacting commercially available 2-fluoro-4-hydroxybenzonitrile withbenzyl bromide. In the compounds of formula (XIV) and R₄ NH₂, R₄ has oneof the meanings given for the formula (I).

The 5(R) and 5(S) enantiomers of the compounds of formula (I) areprepared respectively from the (S) and (R) enantiomers of4-(methoxymethyl)-1,3-dioxolan-2-one of formula (III), according to theprocess described above.

(S)-4-(Methoxymethyl)-1,3-dioxolan-2-one is a known compound, thepreparation of which is described in Patent EP 0,511,031.

(R)-4-(Methoxymethyl)-1,3-dioxolan-2-one is prepared according to thesame method, from (R)-2,2-dimethyl-1,3-dioxolane-4-methanol.

The aim of the following examples is to illustrate the preparation ofsome compounds of the invention. The elemental microanalyses and theN.M.R. spectra confirm the structures of the compounds obtained. In thenames of the compounds, the dash "-" forms part of a word and the dash"₋₋ " is only used for the break at the line end; it is to be omitted inthe absence of a break and must not be replaced either by a normal dashor by a space.

EXAMPLE 1(R)-5-(Methoxymethyl)-3-[6-(phenylmethoxy)benzofuran3-yl]oxazolidin-2-one

1.1. (R)-4-(Methoxymethyl)-2,2-dimethyl-1,3-dioxolane

420 ml of demineralized water and 420 g (10.5 mol) of sodium hydroxidepellets are introduced into a 6-liter reactor equipped with a refluxcondenser, a temperature probe and a dropping funnel. 2.3 1 ofdichloromethane, 396 g (3.00 mol) of(R)-2,2-dimethyl-1,3-dioxolane-4-methanol ([α]_(D) ²⁰ =-11°, c=4,methanol) and 20.5 g (0.090 mol) of benzyltriethyl ammonium chloride areadded to the stirred solution at 20° C. 567 g (4.50 mol) of dimethylsulphate are then added over 50 min, the temperature being maintainedbelow 30° C. The mixture is stirred for 18 hours and then 1 liter ofwater is added. The organic phase is separated and is washed with 0.5 lof water. The aqueous phases are reextracted with 3 l of dichloromethaneand then the organic phases are combined, filtered and concentrated bydistillation under reduced pressure. 496 g of product are obtained.

1.2. (S)-3-Methoxypropane-1,2-diol

A mixture of the 496 g of product obtained in the preceding stage in 220ml of demineralized water is heated to 60° C., with stirring, and then1.5 ml of 36% hydrochloric acid are added. Heating is maintained for 40min and then the mixture is brought to pH 8-9 by addition of 19 ml oftriethylamine. The solvent is evaporated under a pressure of 5.2 kPa, ata temperature of less than 70° C., and then the residue is distilled at61° C. under a pressure of 13 Pa. 246 g of product are obtained.

[α]_(D) ²⁰ =+5.8° (c=4, methanol).

1.3. (R)-4-(Methoxymethyl)-1,3-dioxolan-2-one

245 g (3.31 mol) of (S)-3-methoxypropane-1,2-diol and 560 ml (4.62 mol)of diethyl carbonate are introduced into a round-bottomed flask equippedwith a dropping funnel and a distillation assembly. The mixture isheated to 95° C. and then a sodium methoxide solution, obtained from 10ml of methanol and 0.5 g (0.02 mol) of sodium, is added. The ethanolformed during the reaction is distilled off over 2 hours (vesseltemperature: 95 to 112° C.; column temperature: 82 to 78° C.) and themixture is then cooled and distilled under a pressure of 13 Pa in orderto separate off the excess diethyl carbonate. 267 g of product areobtained.

[α]_(D) ²⁰ =+30.3° (c=1, dichloromethane).

1.4. 2-Hydroxy-4-(phenylmethoxy)benzonitrile

A mixture of 226 g (1.00 mol) of 2-hydroxy-4(phenylmethoxy)benzaldehydein 287 ml (3.83 mol) of nitroethane and of 313 g (2.3 mol) of sodiumacetate in 570 ml of acetic acid is heated at 104° C. for 8 hours and isthen poured into 3 l of a mixture of water and ice. The precipitate isthen filtered off, rinsed with diisopropyl ether and dried. 118 g ofproduct are obtained. Moreover, the filtrate is extracted with diethylether, the organic phase is washed with an aqueous sodiumhydrogencarbonate solution and then with water, dried over sodiumsulphate and concentrated under reduced pressure and the residue is thentriturated in diisopropyl ether. 67 additional g of product are thusobtained.

Melting point: 130° C.

1.5. Ethyl 2-cyano-5-(phenylmethoxy)phenoxyacetate

9.7 g (0.20 mol) of 50% sodium hydride are slowly added portionwise to asolution of 46 g (0.20 mol) of 2-hydroxy-4-(phenylmethoxy)benzonitrilein a mixture of 450 ml of tetrahydrofuran and 450 ml ofdimethylformamide. The mixture is stirred for 30 minutes and then 22.4ml (0.20 mol) of ethyl bromoacetate are added dropwise. Reaction isallowed to take place for 30 minutes, the reaction mixture is thenpoured into ice-cold water and the product is extracted with ethylacetate. The organic phase is then washed with water, dried over sodiumsulphate and concentrated under reduced pressure. After trituration ofthe residue in diisopropyl ether, 50 g of product are obtained.

Melting point: 84° C.

1.6. Ethyl 3-amino-6-(phenylmethoxy)benzofuran-2-carboxylate

50 g (0.16 mol) of ethyl 2-cyano-5-(phenylmethoxy)phenoxyacetate areadded protionwise to a sodium ethoxide solution obtained from 1.8 g(0.080 mol) of sodium and 400 ml of ethanol. The mixture is heated for 1hour at reflux and is then poured into water and the product isextracted with ethyl acetate. The organic phase is then washed with asaturated aqueous sodium chloride solution and is then dried over sodiumsulphate and concentrated under reduced pressure. After purification bychromatography on a silica column with dichloromethane, 40 g of productare obtained.

Melting point: 95° C.

1.7. Ethyl3-[(ethoxycarbonyl)amino]-6-(phenylmethoxy)benzofuran-2-carboxylate

A mixture of 40 g (0.13 mol) of ethyl3-amino-6-(phenylmethoxy)benzofuran-2-carboxylate, 18 ml (0.19 mol) ofethyl chloroformate and 51 g (0.37 mol) of potassium carbonate in 400 mlof benzene is heated at reflux for 18 hours and is then cooled andfiltered and the filtrate is concentrated under reduced pressure. 41 gof product are obtained by recrystallization of the residue fromdiisopropyl ether.

Melting point: 100° C.

1.8. 3-[(Ethoxycarbonyl)amino]-6-(phenylmethoxy)benzofuran-2-carboxylicacid

200 ml of a 10% ethanolic potassium hydroxide solution are added to asolution of 41 g (0.11 mmol) of ethyl3-[(ethoxycarbonyl)amino]-6-(phenylmethoxy)benzofuran-2-carboxylate in400 ml of ethanol. The mixture is heated at reflux for 30 minutes andthe solvent is then evaporated under reduced pressure. The residue istaken up in water and the solution is acidified with hydrochloric acidto pH 2. 41 g of product are obtained by filtration of the precipitateformed.

Melting point: 198° C.

1.9. Ethyl [6-(phenylmethoxy)benzofuran-3-yl]carbamate

A reactor containing 38.6 g (0.11 mol) of3-[(ethoxycarbonyl)amino]-6-(phenylmethoxy)benzofuran-2-carboxylic acidunder nitrogen is immersed in an oil bath at 185-190° C. for 5 minutes.The residue is then taken up in ethyl acetate and the solution is thenwashed with an aqueous potassium hydrogencarbonate solution and thenwith a saturated aqueous sodium chloride solution. The organic phase isthen dried over sodium sulphate, the solvent is evaporated and theresidue is purified on a silica column with a mixture containing 20% ofethyl acetate in cyclohexane. After trituration in diisopropyl ether, 25g of product are obtained.

Melting point: 140° C.

1.10.(R)-5-(Methoxymethyl)-3-[6-(phenylmethoxy)benzofuran-3-yl]oxazolidin-2-one

A mixture of 85 mg (0.6 mmol) of dry potassium carbonate in 40 ml ofanhydrous dimethylformamide is heated to 140° C. and then 1.6 g (12mmol) of (S)-4-methoxymethyl-1,3-dioxolan-2-one and a solution of 2.0 g(6.4 mmol) of ethyl [6-(phenylmethoxy)benzofuran-3-yl]carbamate in 10 mlof dimethylformamide are successively added. The mixture is stirred for3 and a half hours at 140° C. and is then poured into ice-cold water.The product is then extracted with ethyl acetate and the organic phaseis washed with water, dried over sodium sulphate and concentrated underreduced pressure. The residue is purified by chromatography on a silicacolumn with a mixture containing 30% of ethyl acetate in cyclohexane andthen with a mixture containing 2% of ethyl acetate in dichloromethane.After trituration in diisopropyl ether, 1.2 g of product are obtained.

Melting point: 112.6-112.8° C.

[α]_(D) ²⁰ =-34° C. (c=1, dichloromethane).

(S)-5-(Methoxymethyl)-3-[6-(phenylmethoxy)benzofuran-3-yl]oxazolidin-2-onewas obtained from ethyl [6-(phenylmethoxy)benzofuran-3-yl]carbamate and(R)-4-methoxymethyl-1,3-dioxolan-2-one according to the same process.

Melting point: 111.9° C.

[α]_(D) ²⁰ =+33.3° C. (c=1, dichloromethane).

EXAMPLE 2(R)-5-(Methoxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one

1.4 ml (11 mmol) of dimethylphenylamine and 1.9 g (15 mmol) of aluminiumchloride are added to a solution of 1.3 g (3.7 mmol) of(R)-5-(methoxymethyl)-3-[6-(phenylmethoxy)benzofuran-3-yl]oxazolidin-2-onein 50 ml of dichloromethane cooled to 0° C. The mixture is stirred for 1hour, until room temperature is reached, and is then poured into waterand the product is extracted with dichloromethane. The organic phase isthen washed with water, dried over sodium sulphate and concentratedunder reduced pressure. After trituration of the residue in a mixture ofdiisopropyl ether and petroleum ether, 0.64 g of product is obtained.

Melting point: 136.0-136.5° C.

[α]_(D) ²⁰ =-55.3° (c=1, methanol).

(S)-5-(Methoxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one wasobtained from(S)-5-(methoxymethyl)-3-[6-(phenylmethoxy)benzofuran-3-yl]oxazolidin-2-oneaccording to the same process.

Melting point: 141.2° C.

[α]_(D) ²⁰ =+50.5° (c=1, methanol).

EXAMPLE 3(R)-5-(Hydroxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one

17 ml of a 1M solution of boron tribromide in dichloromethane are addedto a solution of 1.5 g (5.7 mol) of(R)-5-(methoxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one in100 ml of dichloromethane cooled to 0° C. The reaction mixture isstirred for 2 hours and is then poured into an aqueous ammonia solution.The product is then extracted with dichloromethane and the organic phaseis then washed with water, dried over sodium sulphate and concentratedunder reduced pressure. After chromatography of the residue on a silicacolumn with a mixture containing 4% of methanol in dichloromethane andtrituration in diethyl ether, 0.80 g of product is obtained.

Melting point: 172.1-172.2° C.

[α]_(D) ²⁰ =-39.3° (c=1, dimethyl sulphoxide).

EXAMPLE 4(R)-5-(Hydroxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-one

A mixture of 0.30 g (1.2 mol) of (R)-5-(hydroxymethyl)-3-(6-hydroxybenzofuran-3 -yl)oxazolidin-2-one, 0.30 g (1.6 mol) of1-bromo-4,4,4-trifluorobutane and 0.33 g (2.4 mol) of potassiumcarbonate in 10 ml of a 2/8 mixture of dimethylformamide andacetonitrile is stirred at 80° C. for 2 hours and is then filtered andthe solvent is evaporated under reduced pressure. The residue is thentaken up in ethyl acetate and the organic phase is then washed withwater, dried over sodium sulphate and concentrated under reducedpressure. After recrystallization from isopropyl alcohol, 0.30 g ofproduct is obtained.

Melting point: 194.0° C.

[α]_(D) ²⁰ =-26.7° (c =1, dimethyl sulphoxide).

EXAMPLE 5(R,R)-5-(Methoxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzofuran-3-yl]oxazolidin-2-one

A mixture of 0.43 g (1.6 mmol) of(R)-5-(methoxymethyl)-3-(6-hydroxybenzofuran-3-yl) oxazolidin-2-one,0.63 g (2.1 mmol) of (R)-4,4,4-trifluoro-3-hydroxybutyl tosylate and0.45 g (3.6 mmol) of potassium carbonate in 40 ml of acetonitrile isstirred at reflux for 2 hours and is then filtered and the filtrate isconcentrated under reduced pressure. The residue is taken up in ethylacetate and the organic phase is then washed with water, dried oversodium sulphate and concentrated under reduced pressure. The residue ispurified by chromatography on a silica column with a mixture containing50% of ethyl acetate in cyclohexane. 0.52 g of product is obtained bycrystallization from a mixture of diethyl ether and hexane.

Melting point: 80.5-82.0° C.

[α]_(D) ²⁰ 5.3° (c =1, dichloromethane).

(S,R)-5-(Methoxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzofuran-3-yl]oxazolidin-2-onewas obtained from(S)-5-(methoxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one and(R)-4,4,4-trifluoro-3-hydroxybutyl tosylate according to the sameprocess.

Melting point: 119.6-119.7° C.

[α]_(D) ²⁰ =+50.8° (c=1, dichloromethane).

EXAMPLE 6(S,R)-5-(Hydroxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzofuran-3-yl]oxazolidin-2-one

0.8 ml of a 1M solution of boron tribromide in dichloromethane is addedto a solution of 100 mg (0.26 mmol) of(S,R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzofuran-3-yl]oxazolidin-2-onein 8 ml of dichloromethane cooled to 0° C. The reaction mixture isstirred for 2 hours and is then poured into an ice-cold aqueous ammoniasolution. The product is then extracted with dichloromethane and theorganic phase is washed with water, dried over sodium sulphate andconcentrated under reduced pressure. After chromatography of the residueon a silica column with a mixture containing 70% of ethyl acetate incyclohexane, 50 mg of product are obtained.

Melting point: 163.9-164.0° C.

[α]_(D) ²⁰ =+57.9° (c=1, dimethyl sulphoxide).

EXAMPLE 7(R)-5-(Methoxymethyl)-3-[6-(cyclopropylmethoxy)benzofuran-3-yl]oxazolidin-2-one

0.50 g (3.6 mmol) of potassium carbonate and 0.20 ml (2.1 mmol) ofbromomethylcyclopropane are added to a solution of 0.47 g (1.8 mmol) of(R)-5-(methoxymethyl)3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one in 40ml of acetonitrile. The reaction mixture is heated at 50-60° C. for 24hours and is then filtered and the solvent is evaporated under reducedpressure. The residue is taken up in dichloromethane, the organic phaseis then washed with water and dried and the solvent is evaporated. Afterchromatography of the residue on a silica column with a mixturecontaining 40% of ethyl acetate in cyclohexane and recrystallizing twicefrom isopropyl alcohol, 0.39 g of product is obtained.

Melting point: 139.9-140.0° C.

[α]_(D) ²⁰ =-39.2° (c=1, dichloromethane).

EXAMPLE 8(R,R)-5-(Methoxymethyl)-3-[6-(5,5,5-trifluoro-4-hydroxypent-1-enyl)benzofuran-3-yl]oxazolidin-2-one

8.1. (R)-3-[5-(Methoxymethyl)-2-oxooxazolidin-3yl]benzofuran-6-yltrifluoromethanesulphonate

5.8 ml (0.035 mol) of trifluoromethanesulphonic anhydride are addedslowly to a solution, maintained at -20° C., of 7.6 g (0.029 mol) of(R)-5-(methoxymethyl)-3-(6-hydroxybenzofuran-3-yl)oxazolidin-2-one in 60ml of pyridine. After returning to room temperature, the mixture ispoured into ice and is brought to a pH of 6 by means of 2N hydrochloricacid. The product is then extracted with ethyl acetate, the solvent isevaporated under reduced pressure and the product is purified bychromatography on silica gel with a 10/90 mixture of cyclohexane anddichloromethane.

10.2 g of product are recovered. Melting point: 98° C.

8.2. Methyl(R)-3-[5-(methoxymethyl)-2-oxooxazolidin-3-yl]benzofuran-6-carboxylate

0.26 g (0.001 mol) of palladium acetate, 12 ml (0.086 mol) oftriethylamine, 86 ml of methanol and 0.48 g (0.001 mol) ofbis(diphenylphosphino)propane are added to a solution of 15.4 g (0.033mol) of (R)-3-[5-(methoxymethyl)-2-oxooxazolidin-3-yl]benzofuran-6-yltrifluoromethanesulphonate in 234 ml of dimethyl sulphoxide. The mixtureis placed under a carbon monoxide atmosphere and is heated for threehours. The mixture is then filtered through celite, the filtrate istaken up in ethyl ether, washed with water and dried over sodiumsulphate and the aqueous phase is evaporated under reduced pressure. Theproduct is purified by chromatography on silica gel with a 99/1 mixtureof dichloromethane and methanol. 5.3 g of product are recovered. Meltingpoint: 116° C.

8.3.(R)-3-[6-(Hydroxymethyl)benzofuran-3-yl]-5-(methoxymethyl)oxazolidin-2-one

22 ml of a 2M solution (0.044 mol) of a borane-dimethyl sulphide complexin tetrahydrofuran are added, in two steps, to a solution of 3.3 g(0.011 mol) of methyl(R)-3-[5-(methoxymethyl)-2-oxooxazolidin-3-yl]benzofuran-6-carboxylatein 40 ml of tetrahydrofuran and the mixture is heated for five hours at55° C. The mixture is hydrolysed with 1N hydrochloric acid. The mixtureis poured into water and the product is extracted with dichloromethane.The organic phase is dried over sodium sulphate and concentrated underreduced pressure. The product is purified by chromatography on silicagel with a 99/1 mixture of dichloromethane and methanol. Aftercrystallization from ethyl ether, 2.0 g of product are recovered.

Melting point: 112° C.

8.4. (R)-3-(6-Formylbenzofuran-3-yl)-5-(methoxymethyl)oxazolidin-2-one

1 ml (14.4 mmol) of dimethyl sulphoxide in 20 ml of dichloromethane isadded to a solution, cooled to -70° C., of 0.75 ml (8.6 mmol) of oxalylchloride in 20 ml of dichloromethane. The mixture is stirred for 15 minand a solution of 2.0 g (7.2 mmol) of(R)-3-[6-(hydroxymethyl)benzofuran-3-yl]-5-(methoxymethyl)oxazolidin-2-onein 35 ml of dichloromethane is slowly added. The mixture is stirred forthree hours at -70° C. and 5.0 ml (36 mmol) of triethylamine are added.After returning to room temperature, the mixture is poured into 50 ml ofwater, the product is extracted with dichloromethane and the organicphase is dried over sodium sulphate and concentrated under reducedpressure. The product is purified by chromatography on silica gel and anoil is recovered which is crystallized from ethyl ether.

1.1 g of product are obtained. Melting point: 94-95° C.

8.5.(R,R)-5-(Methoxymethyl)-3-[6-(5,5,5-trifluoro-4-hydroxypent-1-enyl)benzofuran-3-yl]oxazolidin-2-one

A mixture comprising 0.23 g (0.8 mmol) of(R)-3-(6-formylbenzofuran-3-yl)-5-(methoxymethyl)oxazolidin-2-one, 0.50g (1.0 mmol) of (3-hydroxy-4,4,4-trifluorobutyl)triphenylphosphoniumbromide, 0.16 g (1.2 mmol) of potassium carbonate in 2.5 ml of dioxaneand 0.17 ml of formamide is heated for 24 hours at 80° C. The mixture isthen poured into water, the product is extracted with ethyl acetate andthe organic phase is dried over sodium sulphate and concentrated underreduced pressure. The product is purified by chromatography on silicagel with a 95/5 mixture of dichloromethane and ethyl acetate. Aftertrituration in diisopropyl ether, 0.10 g of pure trans isomer isrecovered. Melting point: 116.5-116.8° C.

[α]_(D) ²⁰ =-15.1° (c=1, dichloromethane).

EXAMPLE 9(R,R)-5-(Methoxymethyl)-3-[6-(5,5,5-trifluoro-4-hydroxypentyl)benzofuran-3-yl]oxazolidin-2-one

0.05 g of palladium-on-charcoal is added to a solution in 8.5 ml ofethanol of 0.26 g (0.67 mmol) of(R,R)-5-(methoxymethyl)-3-[6-(5,5,5-trifluoro-4-hydroxypent-1-enyl)benzofuran-3-yl]oxazolidin-2-oneobtained in Example 8. The mixture is placed under a hydrogen atmospherefor 18 hours, the palladium-on-charcoal is removed by filtration and thefiltrate is concentrated under reduced pressure. The product is thenpurifiedtran by chromatography on silica gel with a 60/40 mixture ofcyclohexane and ethyl acetate. 0.14 g of product is recovered aftercrystallization from diisopropyl ether.

Melting point: 85.8-86.2° C.

[α]_(D) ²⁰ =-18.0° (c=1, dicholoromethane).

EXAMPLE 10(R)-5-(Methoxymethyl)-3-[6-(5,5,5-trifluoropent-1-enyl)benzofuran-3-yl]oxazolidin-2-one

A mixture comprising 0.30 g (1.1 mmol) of(R)-3-(6-formylbenzofuran-3-yl)-5-(methoxymethyl)oxazolidin-2-one, 0.59g (1.3 mmol) of (4,4,4-trifluorobutyl)triphenylphosphonium bromide, 0.21g (1.5 mmol) of potassium carbonate in 3.5 ml of dioxane and 0.22 ml offormamide is heated for six hours at reflux. The mixture is then pouredinto water, the product is extracted with ethyl acetate and the organicphase is dried over sodium sulphate and concentrated under reducedpressure. The product is purified by chromatography on silica gel with a99.5/0.5 mixture of dichloromethane and ethyl acetate. The product iscrystallized from petroleum ether and 0.35 g thereof is recovered in theform of a 67/33 cis/trans mixture.

Melting point: 57-63° C.

[α]_(D) ²⁰ =-36.3° (c=1, dichloromethane).

EXAMPLE 11(R)-5-(Methoxymethyl)-3-[6-(5,5,5-trifluoropentyl)benzofuran-3-yl]oxazolidin-2-one

0.03 g of palladium-on-charcoal is added to a solution in 5 ml ofethanol of 0.13 g (0.35 mmol) of the cis/trans mixture of(R)-5-(methoxymethyl)-3-[6-(5,5,5-trifluoropent-1-enyl)benzofuran-3-yl]oxazolidin-2-oneobtained in Example 10. The mixture is placed under a hydrogenatmosphere for eight hours, the palladium-on-charcoal is then removed byfiltration and the filtrate is concentrated under reduced pressure. Theproduct is then purified by chromatography on silica gel with a 99.5/0.5mixture of dichloromethane and methanol. 0.1 g of product is recovered.

Melting point: 65.7-65.9° C.

[α]_(D) ²⁰ =-31.6° (c=1, dichloromethane).

EXAMPLE 12 (R)-3-(6-Ethenylbenzofuran-3-yl)-5-(methoxymethyl)oxazolidin-2 -one

A mixture of 3.6 g (9.1 mmol) of(R)-3-[5-(methoxymethyl)-2-oxooxazolidin-3-yl]benzofuran-6-yltrifluoromethanesulphonate, 1.1 g (27.3 mol) of lithium chloride, 2.9 g(9.1 mmol) tributylvinyltin and 0.18 g (0.15 mmol) oftetrakis(triphenylphosphine)palladium in 40 ml of dioxane is heated at101° C. The solvent is then evaporated under reduced pressure, theresidue is taken up in ethyl acetate and the organic phase is washedwith water, dried over sodium sulphate and concentrated under reducedpressure. The residue is purified by chromatography on silica gel with a70/30 mixture of cyclohexane and ethyl acetate. 1.9 g of product arerecovered.

Melting point: 89.0-89.1° C.

[α]_(D) ²⁰ =-49.4° (c=1, dichloromethane).

EXAMPLE 13 (R)-5-(Methoxymethyl)-3-[6-(phenylmethoxy)benzo [b]thien-3-yl]oxazolidin-2-one

13.1. Methyl 3-amino-6-methoxybenzo[b]thiophene-2-carboxylate

A solution of 20.3 g (0.363 mol) of potassium hydroxide in 100 ml ofwater is added to a mixture of 36.3 g (0.204 mol) of3-nitro-4-cyanoanisole and 26 g (0.245 mol) of methyl thioglycolate in400 ml of N,N-d-methylformamide, the temperature being maintained at 0°C. The mixture is left stirring at 0° C. for 20 min and is then pouredinto a mixture of water and ice. The precipitate is then filtered off,rinsed with water and dried. The product is dissolved in a mixture ofdichloromethane and tetrahydrofuran, the organic phase is then driedover sodium sulphate and concentrated under reduced pressure and theresidue is triturated in dichloromethane. 26.2 g of product are thusobtained in the form of a light-beige powder.

Melting point: 170° C.

13.2. Methyl3-[(ethoxycarbonyl)amino]-6-methoxybenzo[b]thiophene-2-carboxylate

A mixture of 27.4 g (0.115 mol) of methyl3-amino-6-methoxybenzo[b]thiophene-2-carboxylate, 38 g (0.275 mol) ofpotassium carbonate and 13.2 ml (0.138 mol) of ethyl chloroformate in330 ml of toluene is heated at reflux for three hours. 7 ml (0.069 mol)of ethyl chloroformate are then added and the mixture is left heating atreflux for a further seven hours, with stirring. The mixture is thendiluted with dichloromethane and washed with water. The organic phase isdried over sodium sulphate and the solvent is evaporated under reducedpressure. Recrystallization is carried out from a mixture of isopropanoland diisopropyl ether. 31.2 g of product are obtained.

Melting point: 137° C.

13.3. 3-[(Ethoxycarbonyl)amino]-6-methoxybenzo[b]thiophene-2-carboxylicacid

92 ml of a 10% ethanolic potassium hydroxide solution are added to asolution of 31.4 g (0.101 mol) of methyl3-[(ethoxycarbonyl)amino]-6-methoxybenzo[b]thiophene-2-carboxylate in230 ml of ethanol. The mixture is heated at 60° C. for 10 minutes and isthen poured onto ice-cold water. The mixture is acidified by addition ofa 6N hydrochloric acid solution and the precipitate formed is filteredoff, rinsed with water and dried under reduced pressure. The solid istriturated in ethanol. 22.8 g of product are recovered.

Melting point: 260° C.

13.4. Ethyl (6-methoxybenzo[b]thien-3-yl)carbamate

11.4 g of3-[(ethoxycarbonyl)amino]-6-methoxybenzo[b]thiophene-2-carboxylic acidare heated at 220-225° C. A vitreous gum is obtained which is taken upin tetrahydrofuran until dissolved. The solvent is evaporated underreduced pressure and the residue is purified on a silica column with a10/90 mixture of ethyl acetate and cyclohexane. 19.4 g of product areobtained.

Melting point: 88° C.

13.5. Ethyl (6-hydroxybenzo [b]thien-3-yl)carbamate

46 ml of a 1M solution of boron tribromide (0.046 mol) indichloromethane are added to a solution of 7.7 g (0.031 mol) of ethyl(6-methoxybenzo[b]thien-3-yl)carbamate in 80 ml of dichloromethane,while maintaining the temperature at 0° C. The mixture is allowed toreturn to room temperature and 15 ml of a 1M solution of borontribromide (0.015 mol) in dichloromethane are added. The mixture isstirred for 180 min, neutralization is then carried out with a diluteammonium hydroxide solution and the precipitate obtained is filteredoff. The latter is washed with water and dried. Purification is carriedout by chromatography on a column of silica gel with dichloromethane. 6g of product are obtained.

Melting point: 159-160° C.

13.6. Ethyl [6-(phenylmethoxy)benzo[b]thien-3-yl]carbamate

A mixture comprising 2 g (8.4 mmol) of ethyl(6-hydroxybenzo[b]thien-3-yl)carbamate, 2.16 g (12.6 mmol) of benzylbromide and 2.3 g (16.8 mmol) of potassium carbonate in 30 ml ofacetonitrile is heated at reflux for 11 hours. The mixture is filtered,the solvent is evaporated under reduced pressure and the residue istriturated in petroleum ether. 2.3 g of product are obtained.

Melting point: 129-130° C.

13.7.(R)-5-(Methoxymethyl)-3-[6-(phenylmethoxy)benzo[b]thien-3-yl]oxazolidin-2-one

A mixture comprising 1.1 g (3.36 mmol) of ethyl[6-(phenylmethoxy)benzo[b]thien-3-yl]carbamate, 0.58 g (4.4 mmol) of(S)-4-(methoxymethyl)-1,3-dioxolan-2-one and 46 mg (0.34 mmol) ofpotassium carbonate in 16 ml of N,N-dimethylformamide is brought to 140°C. After 30 min at 140° C., 0.3 g (2 mmol) of(S)-4-(methoxymethyl)-1,3-dioxolan-2-one is added. The mixture is leftat this temperature for a further 210 min, is poured into ice-cold waterand the product is then extracted with dichloromethane. The solvent isremoved under reduced pressure and purification is carried out bychromatography on a column of silica gel with an 80/20 mixture ofcyclohexane and ethyl acetate. 0.15 g of product is obtained in the formof an oil.

[α]_(D) ²⁰ =-18.9° (c=1, dichloromethane).

EXAMPLE 14(R)-5-(Methoxymethyl)-3-[6-(4,4.4-trifluorobutoxy)benzo[b]thien-3-yl]oxazolidin-2-one

14.1. Ethyl [6-(4,4,4-trifluorobutoxy)benzo[b]thien-3-yl]carbamate

A mixture of 2.0 g (8.4 mmol) of ethyl6-hydroxybenzothiophene-3-carbamate (obtained in Stage 13.5. of Example13), 2.4 g (12.6 mmol) of 4,4,4-trifluoro-1-bromobutane and 2.3 g (16.8mmol) of potassium carbonate in 30 ml of acetonitrile is heated atreflux for 90 min. The mixture is evaporated under reduced pressure andthe residue is triturated in petroleum ether. 2.65 g of product areobtained.

Melting point: 103° C.

14.2. (R)-5-(Methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzo[b]thien-3-yl] oxazolidin-2-one

A mixture comprising 1.3 g (3.74 mol) of ethyl[6-(4,4,4-trifluorobutoxy)benzo[b]thien-3-yl]carbamate, 0.64 g (4.8mmol) of (S)-4-(methoxymethyl)-1,3-dioxolan-2-one and 50 mg (0.36 mmol)of potassium carbonate in 16 ml of N,N-dimethylformamide is heated at140° C. for five hours. The solvent is evaporated under reduced pressureand the oil obtained is purified by chromatography on a column of silicagel with an 80/20 mixture of cyclohexane and ethyl acetate. 0.4 g ofproduct is recovered in the form of an oil.

[α]_(D) ²⁰ =-21.8° (c=1, dichloromethane).

EXAMPLE 15(R,R)-5-(Methoxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzo [b]thien-3-yl]oxazolidin-2-one

15.1 Ethyl (R)-3-[[(1,l-dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutanoate

8.36 g (0.123 mol) of imidazole and then 13.5 g (0.09 mol) oft-butyldimethylsilyl chloride are added to a solution of 15.2 g (0.082mol) of ethyl (R)-4,4,4-trifluoro-3-hydroxybutanoate in 75 ml ofN,N-dimethylformamide. The mixture is poured onto 380 ml of water, theproduct is extracted with dichloromethane and the organic phase iswashed with two times 150 ml of water. The product is dried and thesolvent is evaporated under reduced pressure. Purification is carriedout by chromatography on a column of silica gel with a 95/5 mixture ofcyclohexane and ethyl acetate. 20.3 g of a colourless oil are obtained.

[α]_(D) ²⁰ =+32.4° (c=1, methanol).

15.2.(R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutanol

224 ml (0.224 mol) of a 1M diisobutyl aluminium hydride solution areadded to a solution, cooled to -50° C., of 22.4 g (0.0745 mol) of ethyl(R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutanoatein 224 ml of dichloromethane. The mixture is allowed to return to roomtemperature and 15 ml of methanol are added, at -50° C. The mixture isthen poured onto a mixture of 1N hydrochloric acid and ice and theproduct is then extracted with dichloromethane. The organic phase isdried over sodium sulphate and the solvent is evaporated under reducedpressure. 15.6 g of a pale-yellow oil are obtained.

[α]_(D) ²⁰ =+25.9° (c=1, methanol).

15.3. (R)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutyl4-methylbenzenesulphonate

11 mg of dimethylaminopyridine are added to a solution of 15.1 g (0.058mol) of(R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutanol ina mixture of 9.4 ml (0.117 mol) of pyridine and 35 ml of dichloroethane.The mixture is cooled to 0° C. and a solution of 11.4 g (0.06 mol) ofp-methylbenzenesulphonyl chloride in 15 ml of dichloroethane is added.The mixture is left stirring for 48 hours at room temperature. Themixture is poured onto ice-cold water, the product is extracted withdichloromethane, the organic phase is washed with water and dried oversodium sulphate and the solvent is evaporated under reduced pressure. Ayellow oil is recovered which is purified by chromatography on a columnof silica gel with an 80/20 mixture of cyclohexane and dichloromethane.14.9 g of a colourless oil are obtained.

[α]_(D) ²⁰ =+15.7° (c=1, dichloromethane).

15.4. Ethyl (R)-(6-(3-([(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutoxy]benzo [b] thien-3-yl) carbamate

A mixture of 0.3 g (1.26 mmol) of ethyl(6-hydroxybenzo[b]thien-3-yl)carbamate, 0.62 g (1.52 mmol) of(R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutyl4-methylbenzenesulphonate and 0.34 g (2.52 mmol) of potassium carbonatein 5 ml of acetonitrile is heated at reflux for four hours. The mixtureis filtered, the solvent is evaporated under reduced pressure, theproduct is taken up in dichloromethane, the organic phase is washed withwater and dried over sodium sulphate and the solvent is evaporated underreduced pressure. The product is purified by chromatography on a columnof silica gel with a 90/10 mixture of cyclohexane and ethyl acetate. 518mg of a yellow oil are obtained.

15.5.(R,R)-5-(Methoxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzo[b]thien-3-yl]oxazolidin-2-one

A mixture of 1.5 g (0.00314 mol) of ethyl(R)-[6-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4,4-trifluorobutoxy]benzo[b]thien-3-yl]carbamate, 0.415 g (0.00314mol) of (S)-4-(methoxymethyl)-1,3-dioxolan-2-one and 43 mg (0.00031 mol)of potassium carbonate in 15 ml of N,N-dimethylformamide is heated at140° C. for 10 hours. Heating is then carried out for an additional tenhours at 140° C. while adding, in two steps, 0.041 g (0.00031 mol) of(S)-4-(methoxymethyl)-1,3-dioxolan-2-one. The solvent is evaporatedunder reduced pressure, the product is taken up in dichloromethane, theorganic phase is washed with an aqueous sodium chloride solution anddried over sodium sulphate and the solvent is evaporated under reducedpressure. The product thus obtained is mixed with 297 mg (0.14 mmol) oftetra-n-butylammonium fluoride in 15 ml of tetrahydrofuran. The mixtureis stirred at room temperature overnight, the solvent is evaporatedunder reduced pressure and the product is purified by chromatography ona column of silica gel with a 70/30 mixture of cyclohexane and ethylacetate. 150 mg of product are obtained in the form of a yellow oil.

[α]_(D) ²⁰ =-1.8° (c=1, dichloromethane).

EXAMPLE 16(R)-5-(Hydroxymethyl)-3-[6-(4,4.4-trifluorobutoxy)benzo[b]thien-3-yl]oxazolidin-2-one2.3 ml of a 1M solution of boron tribromide

(2.3 mmol) in dichloromethane are added to a solution comprising 0.3 g(0.77 mmol) of(R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzo[b]thien-3-yl]oxazolidin-2-onein 3 ml of dichloromethane, cooled to 0° C. After 150 min, the mixtureis basified with ammonium hydroxide, while maintaining the temperatureat 0° C. The mixture is left stirring for 30 min, the product isextracted with dichloromethane, the organic phase is washed with waterand dried over sodium sulphate and the solvent is evaporated underreduced pressure. Purification is carried out by chromatography on acolumn of silica gel with a 40/60 mixture of cyclohexane and ethylacetate. 289 mg of product are obtained.

Melting point: 107.0-107.2° C.

[α]_(D) ²⁰ =-20.5° (c=1, dichloromethane).

EXAMPLE 17(R)-5-(Methoxymethyl)-3-[1-methyl-6-(phenylmethoxy)-1H-indol-3-yl]oxazolidin-2-one17.1. 2-Fluoro-4-(phenylmethoxy)benzonitrile

A mixture of 40.8 g (0.297 mol) of 2-fluoro-4-hydroxybenzonitrile, 61.06g (0.357 mol) of benzyl bromide and 82 g (0.594 mol) of potassiumcarbonate in 400 ml of acetonitrile is brought to the reflux temperaturefor two hours. The mixture is filtered, the solvent is evaporated underreduced pressure and the evaporation residue is triturated withdiisopropyl ether. 65.5 g of product are recovered.

Melting point: 87° C.

17.2. 2-(Methylamino)-4-(phenylmethoxy)benzonitrile

A solution of 32 g (0.14 mol) of 2-fluoro-4-(phenylmethoxy)benzontirileand of 35 ml of methylamine in 150 ml of ethanol is heated for 32 hoursat 80° C. The reaction mixture is taken up in dichloromethane and theorganic phase is washed three times with water and dried over sodiumsulphate. The solvent is then evaporated under reduced pressure and 32.9g of product are recovered.

Melting point: 120° C.

17.3. Ethyl [[2-cyano-5-(phenylmethoxy)phenyl]methylamino]acetate

64.1 g (0.269 mol) of 2-(methylamino)-4-(phenylmethoxy)benzonitrile in393 ml of ethanol are added to a solution of 39.3 g (0.285 mol) ofpotassium carbonate in 393 ml of water. 152.8 g (0.914 mol) of ethylbromoacetate are then added and the mixture is brought to reflux. After48 hours, the ethanol is evaporated under reduced pressure, the residueis taken up in dichloromethane and the organic phase is washed withwater and dried over sodium sulphate. The solvent is evaporated underreduced pressure and the residue is purified by chromatography on silicagel, elution being carried out with dichloromethane. 19.5 g of productare recovered, which product exists in the form of an oil.

17.4. Ethyl 3-amino-1-methyl-6-(phenylmethoxy)-1H-indole-2-carboxylate

A solution of 28.3 g (0.087 mol) of ethyl([2-cyano-5-(phenylmethoxy)phenyl]methylamino]acetate, in solution in 80ml of tetrahydrofuran, is slowly added to a suspension of 9.8 g (0.087mol) of potassium tert-butoxide in 100 ml of tetrahydrofuran, thetemperature being maintained at less than 30° C. The mixture is leftstirring at room temperature for 25 min and is then poured onto amixture of water and ice. The product is extracted with dichloromethane,the organic phase is washed with water and the solvent is evaporatedunder reduced pressure. The residue thus obtained is triturated inethanol and 22.6 g of product are recovered.

Melting point: 95° C.

17.5. Ethyl3-[(ethoxycarbonyl)amino]-1-methyl-6-(phenylmethoxy)-1H-indole-2-carboxylate

7.5 g (0.088 mol) of sodium hydrogencarbonate and then 8.3 ml (0.076mol) of ethyl chloroformate are added to a solution of 24 g (0.074 mol)of ethyl 3-amino-1-methyl-6-(phenylmethoxy)-1K-indole-2-carboxylate in180 ml of a 9/1 mixture of tetrahydrofuran and water, while maintainingthe temperature below 25° C. The mixture is left at room temperature forone hour and the solvent is then evaporated under reduced pressure. Theresidue is taken up in dichloromethane, washed with water and dried oversodium sulphate and the solvent is evaporated under reduced pressure.28.2 g of product are recovered.

Melting point: 124-125° C.

17.6.3-[(Ethoxycarbonyl)amino]-1-methyl-6-(phenylmethoxy)-1H-indole-2-carboxylicacid

A suspension of 28.1 g (0.0708 mol) of ethyl3-[(ethoxycarbonyl)amino]-1-methyl-6-(phenylmethoxy)-1H-indole-2-carboxylatein 170 ml of 96° ethanol is brought to reflux. 64 ml of a 10% ethanolicpotassium hydroxide solution and 50 ml of tetrahydrofuran are added tothis mixture. The suspension is left at reflux for 150 min, is thenconcentrated under reduced pressure, diluted with a mixture of water andice and acidified with 6N hydrochloric acid. The product is thenextracted with a mixture of dichloromethane and tetrahydrofuran, theorganic phase is washed with water and dried over sodium sulphate andthe solvent is evaporated under reduced pressure. The residue istriturated in diisopropyl ether and 24.8 g of product are recovered.

Melting point: 180° C. (decomposition).

17.7. Ethyl (1-methyl-6-(phenylmethoxy)-1H-indol-3-yl)carbamate

24.6 g (0.066 mol) of3-[(ethoxycarbonyl)amino]-1-methyl-6-(phenylmethoxy)-1H-indole-2-carboxylicacid are heated at a temperature of the order of 180-185° C. for threeminutes, the residue is then triturated in tetrahydrofuran and filteredand the filtrate is concentrated under reduced pressure. The product ispurified by chromatography on silica gel, elution being carried out withan 80/20 mixture of cyclohexane and ethyl acetate. 18.3 g of product arerecovered.

Melting point: 140-142° C.

17.8.(R)-5-(Methoxymethyl)-3-[l-methyl-6-(phenylmethoxy)-1H-indol-3-yl]oxazolidin-2-one

A mixture comprising 9.1 g (0.028 mol) of ethyl[1-methyl-6-(phenylmethoxy)-1H-indol-3-yl)carbamate, 6.6 g (0.05 mol) of(S)-4-(methoxymethyl)-1,3-dioxolan-2-one and 1.16 g (0.0084 mol) ofpotassium carbonate in 180 ml of N,N-dimethylformamide is heated for 14hours at 140° C. The solvent is evaporated under reduced pressure andthe product is purified by chromatography on silica gel with a 50/50mixture of cyclohexane and ethyl acetate. 6 g of product are recovered,which product exists in the form of a gum.

[α]_(D) ²⁰ =-44.1° (c=1, methanol).

(S)-5-(Methoxymethyl)-3-[l-methyl-6-(phenylmethoxy)-1H-indol-3-yl]oxazolidin-2-onewas prepared from (R)-4-(methoxymethyl)-1,3-dioxolan-2-one according tothe same process, which product exists in the form of an oil.

[α]_(D) ²⁰ =+41.5° (c=1, methanol).

EXAMPLE 18(S,R)-5-(Methoxymethyl)-3-[1-methyl-6-(4,4.4-trifluoro-3-hydroxybutoxy)-1H-indol-3-yl]oxazolidin-2-one

18.1.(S)-5-(Methoxymethyl)-3-[l-methyl-6-hydroxy-1H-indol-3-yl]oxazolidin-2-one

A solution of 1 g (0.0027 mol) of(S)-5-(methoxymethyl)-3-[1-methyl-6-(phenylmethoxy)-1H-indol-3-yl]oxazolidin-2-one,obtained in Example 17, in a mixture of 15 ml of N,N-dimethylformamideand 15 ml of ethanol is catalytically hydrogenated. The hydrogenation iscarried out for 18 hours, under a normal hydrogen pressure, in thepresence of 0.2 g of palladium-on-charcoal. The reaction mixture isfiltered to remove the palladium-on-charcoal, the solvent is evaporatedunder reduced pressure and 0.53 g of product is recovered, which productexists in the form of a gum.

18.2.(S,R)-5-(Methoxymethyl)-3-[1-methyl-6-(4,4,4-trifluoro-3-hydroxybutoxy)-1H-indol-3-yl]oxazolidin-2-one

A mixture of 0.30 g (0.00108 mol) of(S)-5-(methoxymethyl)-3-[1-methyl-6-hydroxy-1-H-indol-3-yl]oxazolidin-2-one,0.34 g (0.00114 mol) of (R)-4,4,4-trifluoro-3-hydroxybutyl tosylate and0.3 g (0.00217 mol) of potassium carbonate in 5 ml of acetonitrile isstirred at reflux for 90 min. The mixture is then diluted withdichloromethane and filtered and the filtrate is concentrated underreduced pressure. The organic phase is washed with water, dried oversodium sulphate and evaporated under reduced pressure. The residue ispurified by chromatography on a silica column with a 95/5 mixture ofdichloromethane and methanol. 0.27 g of product is recovered, whichproduct exists in the form of gum.

Melting point: 80.5-82.0° C.

[α]_(D) ²⁰ =+68.1° (c=1, methanol).

Compounds according to the invention and their physical characteristicsare listed in the following table. These compounds were preparedaccording to the processes described above. In the solvent column, thesolvent used to measure the optical rotation [α] ²⁰ has been shown (withc=1, except when otherwise indicated).

                                      TABLE                                       __________________________________________________________________________                                 (I)                                                                           1  STR3##                                           -                                                                          No.                                                                              R.sub.1 Z      R.sub.2                                                                          X   Config. M.p.                                                                       (° C.)                                                                       [α].sub.D.sup.20                                                            Solvent                               __________________________________________________________________________      1 2                                                                                                                 2  CH.sub.3 O  5(R) 5(S)                                                      112.6-112.8 111.9  -34°                                                +33.3°  dichloromethane                                                dichloromethane                          -  3 HO CH.sub.3 O 5(R) 136.0-136.5 -55.3° methanol                    4    5(S) 141.2 +50.5° methanol                                        5 HO H O 5(R) 172.1-172.2 -39.3° dimethyl sulphoxide                   6    5(S) 188.1-188.2 +39.9 dimethyl sulphoxide                               7 CF.sub.3 --(CH.sub.2).sub.3 O CH.sub.3 O 5(R) 92.6-93.0 -30.3°                                             dichloromethane                         8    5(S) 93.6 +28.6° dichloromethane                                  9 CF.sub.3 --(CH.sub.2).sub.3 O H O 5(R) 194.0 -26.7° dimethyl                                              sulphoxide                              10    5(S) 194.0-194.1 +27.5° dimethyl sulphoxide                      11 CF.sub.3 --CH(OH)--(CH.sub.2).sub.2 O CH.sub.3 O 3(R), 5(R) 80.5-82.0                                             -5.3° dichloromethane                                                  12    3(R), 5(S) 119.6-119.7                                                 +50.8° dichloromethane                                                  13 CF.sub.3 --CH(OH)--(CH.sub.2).                                            sub.2 O H O 3(R), 5(R) 146-148                                                -2.4° dimethyl sulphoxide                                               14    3(R), 5(S) 163.9-164.0                                                 +57.9° dimethyl sulphoxide       15 CF.sub.3 --CH(OH)--(CH.sub.2).sub.2 O CH.sub.3 O 3(S), 5(R) 119.7-119                                            .8 -51.1° dichloromethane                                               16    3(S), 5(S) 81.1-81.7                                                   +5.3° dichloromethane                                                   17 CF.sub.3 --CH(OH)--CH.sub.2 O                                             CH.sub.3 O 5(R) 99.2-99.4                                                     -28.6° dichloromethane                                                  18 CH.sub.3 --(CH.sub.2).sub.3 O                                             CH.sub.3 O 5(R) 72.3-72.4 -35.0                                               dichloromethane                         19 CN--(CH.sub.2).sub.3 O CH.sub.3 O 5(R) 90.8-90.9 -33.7°                                                   dichloromethane                          - 20 21                                                                                                            3  CH.sub.3 O  5(R) 5(S)                                                      139.9-140.0 141.5  -39.2°                                              +35.3°  dichloromethane                                                dichloromethane                          - 22                                                                                                               4  CH.sub.3 O 5(R) 85.1-85.5                                                  -30.8° dichloromethane                                                   - 23                                                                        5  CH.sub.3 O 5(R) 92.7-92.8                                                  -31.0° dichloromethane                                                   - 24                                                                        6  H O 5(S) 171.4-171.6 +29.1.degr                                            ee. dimethyl sulphoxide                  - 25 CH.sub.3 CH(OH)--(CH.sub.2).sub.2 O CH.sub.3 O 5(S) 63.0-63.3                                                 +33.1° dichloromethane                                                  26    5(R) 65.3-65.6 -34.0.degree                                            . dichloromethane                        - 27                                                                                                               7  CH.sub.3 O 5(S) 67.2-67.8                                                  +28.8° dichloromethane                                                   - 28                                                                        8  CH.sub.3 O 5(S) 100.6-101.0                                                +31.0° dichloromethane                                                   - 29                                                                        9  CH.sub.3 O 5(S) 126.6 +30.2.deg                                            ree. dichloromethane                     - 30                                                                                                               0  CH.sub.3 O 5(S) 161.3-161.6                                                +28.4 dichloromethane                    - 31                                                                                                               1  CH.sub.3 O 5(S) 104.6 +29.7.deg                                            ree. dichloromethane                     - 32                                                                                                               2  CH.sub.3 O 5(S) 107.9-108.5                                                +30.6 dichloromethane                    - 33                                                                                                               3  CH.sub.3 O 5(R) 126.4-126.5                                                -29.8° dichloromethane                                                   - 34                                                                        4  CH.sub.3 O 5(S) 94.0-94.1                                                  +31.1° dichloromethane                                                   - 35 36                                                                     5  CH.sub.3 O  5(R) 5(S)                                                      118.3-118.7 117.2-117.4  -31.7.deg                                            ree. +31.2°  dichloromethan                                            e dichloromethane                        - 37 H.sub.3 C═CH CH.sub.3 O 5(R) 89.0-89.1 -49.4° dichlorom                                            ethane                                  38 CF.sub.3 CH(OH)CH.sub.2 CH═CH CH.sub.3 O 3(R), 5(R) 116.5-116.8                                              -15.1° dichloromethane                                                      trans                              39 CF.sub.3 CH(OH)CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 O 3(R), 5(R)                                                  85.8-86.2 -18.0° dichlorome                                            thane                                   40 CF.sub.3 --CH.sub.2 CH.sub.2 --CH═CH CH.sub.3 O 5(R), 57-63                                                  -36.3° dichloromethane                                                      cis/trans                          41 CF.sub.3 --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 O 5(R)                                                   65.7-65.9 -31.6° dichlorome                                            thane                                   42 2-phenylethenyl CH.sub.3 O 5(R), 179.0-179.6 -34.4° dimethyl                                              sulphoxide                                  trans                                                                     43 2-phenylethyl CH.sub.3 O (R) 97.0-97.3 -35.4° dichloromethane       44 CF.sub.3 --(CH.sub.2).sub.3 O H S 5(R) 107.0-107.2 -20.5°                                                 dichloromethane                         45 CF.sub.3 --(CH.sub.2).sub.3 O CH.sub.3 S 5(R) oil -21.8°                                                  dichloromethane                         46    5(S) oil +21.1° dichloromethane                                  47 C.sub.6 H.sub.5 --CH.sub.2 O CH.sub.3 S 5(R) oil -18.9°                                                   dichloromethane                         48    5(S) 73.8-74.2 +23.9° dichloromethane                            49 CF.sub.3 --CH(OH)(CH.sub.2).sub.2 O CH.sub.3 S 3(R), 5(R) oil                                                    -1.8° dichloromethane                                                   50    3(R), 5(S) oil +3.9°                                             dichloromethane                        51 C.sub.6 H.sub.5 --CH.sub.2 O CH.sub.3 NCH.sub.3 5(R) oil -44.1.degree                                            . methanol                              52    5(S) oil +41.5° methanol                                         53 CF.sub.3 --(CH.sub.2).sub.3 O CH.sub.3 NCH.sub.3 5(R) oil -37.0.degre                                            e. methanol                             54    5(S) oil +36.7° methanol                                         55 CF.sub.3 --CH(OH)--(CH.sub.2).sub.2 O CH.sub.3 NCH.sub.3 3(R), 5(R)                                              oil -9.6° methanol                                                      56    3(R), 5(S) oil +68.1.degree                                            . methanol                            __________________________________________________________________________     .sup.(a) : c = 0.5                                                            In the table, the notation 3(R) or 3(S) relates to the configuration of       the chiral carbon of the R.sub.1 Z group and the notation 5(R) or 5(S)        relates to the configuration of the chiral carbon in the 5position of the     oxazolidinone ring.                                                      

The compounds of the invention have formed the subject ofpharmacological tests which make it possible to determine theirinhibiting power for monoamine oxidase A and for monoamine oxidase B.

The MAO-A and MAO-B activities were measured in vitro by using a ratbrain homogenate as enzyme source, according to the method described byC. Fowler and M. Strolin-Benedetti in J. Neurochem., 40, 1534-1541(1983).

The standard quantitative determination consists in homogenizing the ratbrain in 20 volumes of 0.1M phosphate buffer (pH=7.4) and inpreincubating 100 μl of homogenate (5 mg of tissue) at 37° C. for 20minutes, in the absence or in the presence of different concentrationsof the inhibitor studied. The reaction is initiated by the addition of[¹⁴ C]serotonin ([¹⁴ C]5HT, final concentration 125 μM), for themeasurement of the MAO-A activity, or of [¹⁴ C]phenylethylamine ([¹⁴C]PEA, final concentration 8 μM), for the measurement of the MAO-Bactivity, in a final volume of 500 μl. After incubating for 5 minutes inthe case of [¹⁴ C]5HT and incubating for 1 minute in the case of [¹⁴C]PEA, the reaction is halted by addition of 200 μl of 4N hydrochloricacid. The radioactive metabolites resulting from the oxidativedeamination are then separated from the unconverted substrate, byextraction into an organic phase, and quantified by counting theradioactivity. The inhibitory activities with respect to MAO-A and MAO-Bare given respectively by the inhibition constants Ki (MAO-A) and Ki(MAO-B). For the compounds of the invention, the Ki (MAO-A) values varybetween 1.2 nM and values greater than 1000 nM whereas the Ki (MAO-B)values vary between 0.3 nM and values greater than 1000 nM. Somecompounds of the invention are selective inhibitors of MAO-B, it beingpossible for the Ki (MAO-A)/Ki (MAO-B) ratio to be greater than 10³.Some compounds of the invention are selective inhibitors of MAO-A, itbeing possible for the Ki (MAO-B)/Ki (MAO-A) ratio to be greater than10³. Others are mixed inhibitors of MAO-A and of MAO-B, it beingpossible for the Ki (MAO-A)/Ki (MAO-B) ratio to be between 0.1 and 10.

The results obtained show that the compounds of the invention can beused for the preparation of medicaments which are selective inhibitorsof MAO-A or of MAO-B or which are mixed inhibitors of MAO-A and ofMAO-B, these medicaments being employed in therapeutics, in particularin the treatment of depressive states of any nature, senile depressivepsychoses, hypobulia, social phobias or mood disorders, in theimprovement in general cerebral behaviour, in the prevention and thetreatment of neurodegenerative diseases, such as Parkinson's disease andAlzheimer's disease, and all memory disorders, in anxiety, panicattacks, treatment of dependence and weaning related to the consumptionof alcohol, of tobacco and/or of narcotics, and loss of appetite.

The compounds of the invention can be presented, in combination withexcipients, in the form of compositions formulated for the purpose oforal, parenteral or rectal administration, for example in the form oftablets, dragees, capsules, solutions, suspensions or suppositories.

The dose of active principle administered is generally between 0.01 and50 mg/kg/day, taken one or a number of times. ##STR18##

We claim:
 1. A compound of formula (I) in which:R₁ represents a hydrogenatom, an alkyl group, a hydroxyalkyl group, a fluoroalkyl group, ahydroxyfluoroalkyl group, a cyanoalkyl group, a phenyl group which isunsubstituted or substituted by a halogen atom or by an alkoxy, nitrileor nitro group, a phenylmethyl group which is unsubstituted orsubstituted by a halogen atom or by an alkoxy, nitrile or nitro group oran R₃ A- group in which R₃ is a cycloalkyl or cyclooxyalkyl group whichis unsubstituted or substituted by a hydroxyl group and A is a --CH₂ or--CH₂ --CH₂ radical, R₂ represents a hydrogen atom or a methyl group, Xrepresents an oxygen or sulphur atom or an NR₄ group where R₄ is analkyl group or a hydrogen atom and Z represents an oxygen atom or a--CH═CH or --CH₂ --CH₂ group,the said compounds existing in the form ofpure enantiomers or diastereoisomers or of a mixture of these differentforms.
 2. A compound according to claim 1, wherein R₂ is a methyl group.3. A compound according to claim 2, wherein X represents an oxygen atom.4. A compound according to claim 1 wherein, when X represents an oxygenatom, the R₁ Z group represents:either, i) an R_(a) O group, where R_(a)has one of the meanings of R₁ chosen from a hydrogen atom, an alkylgroup, a fluoroalkyl group, a hydroxyfluoroalkyl group, a cyanoalkylgroup, an R₃ A- group, a phenyl group which is unsubstituted orsubstituted by a halogen atom or a nitro, nitrile or alkoxy group and aphenylmethyl group which is unsubstituted or substituted by a halogenatom or a nitro, nitrile or alkoxy group, or, ii) an R_(b) Z group,where Z is a --CH═CH-- or --CH₂ --CH-- group and R_(b) has one of themeanings of R₁ chosen from a hydrogen atom or an alkyl group, afluoroalkyl group, a hydroxyalkyl group, a hydroxyfluoroalkyl group, aphenyl group which is unsubstituted or substituted by a halogen atom ora nitro, nitrile or alkoxy group or a phenylmethyl group which isunsubstituted or substituted by a halogen atom or a nitro, nitrile oralkoxy group.
 5. A compound according to claim 4, wherein R_(a) is ahydrogen atom or a phenylmethyl, butyl, 4,4,4-trifluorobutyl,4,4,4-trifluoro-3-hydroxybutyl, 3,3,3-trifluoro-2-hydroxypropyl,3-cyanopropyl, p-fluorophenylmethyl, cyclopropylmethyl or2-(1-hydroxycyclopentyl)ethyl group.
 6. A compound according to claim 4,wherein R_(b) Z is chosen from the ethenyl, 2-phenylethenyl,2-phenylethyl, 5,5,5-trifluoropentyl, 5,5,5-trifluoropentenyl,5,5,5-trifluoro-4-hydroxypentyl or 5,5,5-trifluoro-4-hydroxypentenylgroup.
 7. A compound according to claim 1 wherein, when X represents asulphur atom, the R₁ Z group represents an R_(c) O group, where R_(c)has one of the meanings of R₁ chosen from an alkyl group, a hydroxyalkylgroup, a fluoroalkyl group, a hydroxyfluoroalkyl group, a phenyl groupwhich is unsubstituted or substituted by a halogen atom or a nitro,nitrile or alkoxy group or a phenylmethyl group which is unsubstitutedor substituted by a halogen atom or by an alkoxy, nitrile or nitrogroup.
 8. A compound according to one of claim 1, wherein, when Xrepresents an NR₄ group, R₄ is a methyl group and the R₁ Z grouprepresents an R_(d) O group, where R_(d) has one of the meanings of R₁chosen from a fluoroalkyl group, a hydroxyfluoroalkyl group, a phenylgroup which is unsubstituted or substituted by a halogen atom or anitro, nitrile or alkoxy group or a phenylmethyl group which isunsubstituted or substituted by a halogen atom or a nitro, nitrile oralkoxy group.
 9. A compound according to claim 1, wherein, when Zrepresents a --CH═CH group and R₁ does not represent a hydrogen atom,the said compounds exist in the cis or trans form or in the form of acis/trans mixture. 10.(R)-5-(Methoxymethyl)-3-[6-(phenylmethoxy)benzofuran-3-yl]oxazolidin-2-oneor its enantiomer. 11.(R)-5-(Methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-oneor its enantiomer. 12.(R,R)-5-Methoxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzofuran-3-yl]oxazolidin-2-one or its diastereoisomers. 13.(R,R)-5-(Hydroxymethyl)-3-[6-(4,4,4-trifluoro-3-hydroxybutoxy)benzofuran-3-yl]oxazolidin-2-oneor its diastereoisomers. 14.(R)-5-(Methoxymethyl)-3-[6-(5,5,5-trifluoropentyl)benzofuran-3-yl]oxazolidin-2-oneor its enantiomer. 15.(R)-5-(Methoxymethyl)-3-[6-(5,5,5-trifluoro-4-hydroxypent-1-enyl)benzofuran-3-yl]-oxazolidin-2-one,its diastereoisomers or their cis or trans isomers. 16.(R)-5-(Methoxymethyl)-3-[6-(phenylmethoxy)benzo[b]thien-3-yl]oxazolidin-2-oneor its enantiomer.
 17. A compound according to claim 1, wherein thecompoundis(R)-5-(Methoxymethyl)-3-[6-(cyclopropylmethoxy)benzofuran-3-yl]oxazolidin-2-oneor its enantiomer,(R)-5-(Methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzo[b]thien-3-yl]oxazolidin-2-oneor its enantiomer,(R)-3-(6-Ethenylbenzofuran-3-yl)-5-(methoxymethyl)oxazolidin-2-one orits enantiomer,(R)-5-(Methoxymethyl)-3-[6-tetrahydropyranyl-methoxy)benzofuran-3-yl]oxazolidin-2-oneor its enantiomer,(R)-5-(Methoxymethyl)-3-[6-[4-cyano(propyloxy)]benzofuran-3-yl]oxazolidin-2-oneor its enantiomer,(R)-5-(Methoxymethyl)-3-[6-[4-methoxy(phenylmethoxy)]benzofuran-3-yl]oxazolidin-2-oneor its enantiomer, or(R)-5-(Methoxymethyl)-3-[6-[3-chloro(phenylmethoxy)]benzofuran-3-yl]oxazolidin-2-oneor its enantiomer.
 18. Process for the preparation of A compoundaccording to claim 3 wherein an ethyl carbamate derivative of formula(II) ##STR19## where R₁ represents an alkyl group, a hydroxyalkyl group,a fluoroalkyl group, a hydroxyfluoroalkyl group, a cyanoalkyl group, aphenyl group which is unsubstituted or substituted by a halogen atom orby an alkoxy, nitrile or nitro group, a phenylmethyl group which isunsubstituted or substituted by a halogen atom or by an alkoxy, nitrileor nitro group or an R₃ A-group in which R₃ is a cycloalkyl orcyclooxyalkyl group which is unsubstituted or substituted by a hydroxylgroup and A is --CH₂ or --CH₂ --CH₂ radical, and X represents an oxygenor sulphur atom or an NR₄ group where R₄ is an alkyl group or a hydrogenatom, is reacted, in the presence of potassium carbonate, with4-(methoxymethyl)-1,3-dioxolan-2-one of formula (III). ##STR20## 19.Medicament comprising a compound according to claim
 1. 20.Pharmaceutical composition, comprising a compound according to claim 1,in combination with at least one pharmaceutically acceptable excipient.